Gestational diabetes mellitus prevalence in Brazil: a systematic review and meta-analysis

Abstract: This study estimates gestational diabetes mellitus prevalence in Brazil. A systematic review was conducted with articles published between 2010 and 2021 on the PubMed, Scopus, Google Scholar, SciELO, LILACS and Virtual Health Library databases, as well as gray literature. Data were extracted using a standardized instrument together with the risk of bias assessment tool proposed by Hoy et al. A meta-analysis with robust variance and random effects was developed. Heterogeneity was verified using I2 and publication bias was assessed using funnel plot and Egger’s test. Prevalence according to risk of bias, diagnostic criteria and country’s regions was determined by subgroup analyses. A total of 32 studies were included, representing 21,942 women. gestational diabetes mellitus pooled prevalence was 14% (95%CI: 11.0; 16.0), considerably higher than estimates from previous studies. Regarding risk of bias, studies with low, medium, and high risk showed a pooled prevalence of 12%, 14% and 14%, respectively. Overall GRADE certainty of evidence rating was low. Most studies used the International Association of Diabetes in Pregnancy Study Group (IADPSG) criteria or the adapted IADPSG, showing a pooled prevalence of 15% and 14%, respectively. As for region, the pooled prevalence was higher in the Southeast (14%) and lower in the Central-West (9%). This is the first systematic review to provide evidence on gestational diabetes mellitus prevalence at a national level and to demonstrate considerable heterogeneity among articles and the influence of region, diagnostic criteria and study quality on the referred indicator.


Introduction
Gestational diabetes mellitus consists in the state of hyperglycemia during pregnancy with glycemic levels that indicate no previous diabetes mellitus diagnosis 1 .Its development involves factors such as a state of insulin resistance and hormonal and metabolic changes caused by the body's adaptation to the fetal needs, as well as nutritional and genetic factors 2 .Gestational diabetes mellitus is one of the leading causes of morbidity and mortality in pregnant women and newborns, representing a global public health issue with repercussions for the maternal-fetal binomial 3 , such as childhood obesity or type 2 diabetes mellitus.Consequently, it results in higher public health expenses which could be avoided with early diagnoses and effective interventions to aid pregnant women during this period 3,4 .
Gestational diabetes mellitus has several diagnostic criteria resulting in a high diversity for its estimated prevalence.The American Diabetes Association (ADA) and the World Health Organization (WHO) recommend adopting the International Association of Diabetes in Pregnancy Study Group (IADPSG) diagnostic criteria for gestational diabetes mellitus diagnosis, confirmed by testing the levels of fasting blood glucose or using oral glucose tolerance test (OGTT) 75g between 24-28 weeks of pregnancy, period in which insulin resistance is significantly increased 5 .In 2013, WHO extended the IADPSG criterion validity for any gestational age and established OGTT values after 2 hours up to 199mg/dL, thus avoiding convergence with the diabetes mellitus criteria 1 .
Globally, gestational diabetes mellitus prevalence varies between 0.3% and 28% 6 .In 2015, approximately 17.8 million deliveries with neonates born alive to pregnant women between 20 and 49 years old were affected by this condition 7 .In Brazil, prevalence data show considerable variability as shown by a multicenter cohort study with 5,564 pregnant women that estimated a 18% prevalence (95% confidence interval -95%CI: 16.9; 19.0) 8 , whereas a cohort research with 4,131 participants observed a 2.6% prevalence (95%CI: 2.1; 3.1) 9 , despite being based on self-reported answers.
The lack of systematic reviews and meta-analyses on gestational diabetes mellitus in Brazil, as well as the impact of this clinical outcome on national health, justifies an in-depth investigation of observational studies conducted in the country.In this context, this article estimated the gestational diabetes mellitus pooled prevalence in Brazil, a relevant data to subsidize planning and administration of interventions such as public policies, health services and programs aimed at reducing the level of gestational diabetes mellitus impact and improving mother and child health 10,11 .Additionally, it categorized the pooled prevalence evaluation according to country region, the gestational diabetes mellitus diagnostic criteria used and the risk of bias in the analyzed articles.

Outcomes and diagnostic criteria
Gestational diabetes mellitus prevalence was obtained by calculating the ratio between the number of pregnant women diagnosed with gestational diabetes mellitus and the total number of pregnant women in the studied sample.Gestational diabetes mellitus diagnostic criteria varied between articles.IADPSG criterion was attributed when the study followed the definition below or cited its use: fasting blood glucose ≥ 92mg/dL and ≤ 125mg/dL at the first prenatal visit or at least one of the OGTT with 75g values of ≥ 92mg/dL in fasting, ≥ 180mg/dL after one hour and ≥ 153mg/dL after two hours, performed between 24 and 28 weeks of gestation 1 .Adapted IADPSG was considered when the article adopted the specifications above with some alteration in the testing period or blood glucose values.The 2010 ADA criterion was met if gestational diabetes mellitus diagnosis was confirmed with an OGTT 100g value greater than or equal to at least two of the values: 95mg/dL in fasting, 180mg/dL after one hour, 155mg/dL after two hours, and 140mg/dL after three hours 12 .Studies that made the diagnosis using fasting plasma glucose ≥ 126mg/dL and/or OGTT 75g ≥ 140mg/dL after two hours followed the 1999 WHO guidelines 1 .The Brazilian Diabetes and Pregnancy Task Force (GTDG, acronym in Portuguese) 2001 criterion corresponds to diagnosis based on fasting glucose ≥ 110mg/dL or OGTT 75g ≥ 140mg/dL after two hours 13 .Finally, articles that did not inform or that did not specify the adopted diagnostic criteria were listed as not informed and non-accurate criteria, respectively.

Quality evaluation
Study quality was assessed by analyzing risk of bias based on a tool developed by Hoy et al. 14 which has been used in systematic reviews aiming to assess the prevalence of a health problem or event 10,15,16 .The instrument consists of ten items that address four different bias domains and an overall summary assessment based on the responses to the previous items.Their topics correspond Cad.Saúde Pública 2024; 40(8):e00064919 to external (items 1 to 4, whose domains are selection and non-response bias) and internal (items 5 to 10, whose domains are measurement and analysis) study validity dimensions 14 .Each article was classified according to the answers to individual items: "yes", if the item was answered or "no", if the information was insufficient or not contemplated, resulting in a final classification depending on the added result: 8 or more "yes" answers indicated low risk of bias; 6 to 7 "yes" answers, moderate; and 5 or less "yes" answers a high risk of bias.Similar categorization was used in other systematic review studies 10,16 .Some conventions were adopted to standardize the risk of bias classification.Regarding external validity, study of local population, exclusion criteria selective to a certain population or use of a convenience sample were considered high risk.As for internal validity, information obtained from only one source (e.g., only from medical records), unspecified diagnostic criteria, different data collection between individuals in the sample, unspecified time of diagnosis (gestational week) or no information on the numerator and denominator used to calculate prevalence indicated high risk.
The GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) assessment tool for prognosis studies was used to rate the certainty of the evidence generated 17 .A summary of findings was developed, explaining the decision regarding the five criteria (risk of bias, inconsistency, imprecision, indirectness and publication bias).

Data analysis
All eligible studies were included in the systematic review for constructing a database based on the collection instrument.We developed a meta-analysis with robust variance and random effects using the Stata software, version 16 (https://www.stata.com), in which we prepared the forest plot and estimated the summary measure for the pooled prevalence data together with its confidence interval.Heterogeneity between studies was verified by calculating I 2 variability (low < 25%, moderate 25-50% and high > 50%).Gestational diabetes mellitus pooled prevalence for each country region and according to risk of bias was estimated by subgroup analyses.Pooled prevalence was also analyzed according to the gestational diabetes mellitus diagnostic criteria used.Publication bias was verified by a funnel plot, Egger's test and trim-and-fill sensibility analysis.Finally, a meta-regression analysis for random effects was performed to verify trends over time considering the years of data collection.The first year was considered when the study presented a data collection longer than one year.Articles lacking this information were excluded from the meta-regression analysis.

Results
Figure 1 summarizes the selection process for the studies included in this systematic review.A total of 3,121 articles were identified, 3,120 from five different databases and 1 retrieved from gray literature.By reading the titles and abstracts, 273 duplicates were identified resulting in 2,848 studies for screening.Of these, 2,776 articles were excluded in a later evaluation for not addressing the research topic, not presenting prevalence data, and not considering Brazil as the source of analysis.Of the 71 articles pre-selected for reading, 39 were removed for meeting the exclusion criteria thus totaling 32 studies included in the review.
Total sample consisted of 21,942 women from four different Brazilian regions.Seven studies were conducted in the Northeast, two in the Central-West, 11 in the Southeast and ten in the Southern region (Table 1).Regarding study design, 17 were cross-sectional studies, 13 were prospective cohort studies and four were retrospective cohort studies.
Gestational diabetes mellitus prevalence ranged from 1.6% to 40.2%.As for the gestational diabetes mellitus diagnostic criteria, 14 studies used the IADPSG adapted, five used the IADPSG, two the WHO 1999, two the ADA 2010, one the GTDG 2001, and one failed to specify the criterion used.Additionally, seven studies failed to report the criteria used for gestational diabetes mellitus diagnosis (Table 1).
Cad. Saúde Pública 2024; 40(8):e00064919 Risk of bias analysis based on the instrument by Hoy et al. 14 found that five studies (15.6%) had a low risk of bias, 13 (37.5%)had a moderate risk of bias and 15 (46.8%) a high risk (Table 2).As 28 (82.4%)out of the 34 articles were characterized as moderate or high risk of bias, this indicates a vulnerability of the studies.The item with the highest frequency of "no" answers referred to the use of a representative sample (84.3%), whereas the item with the most "yes" answers concerns the use of the same diagnostic method for all evaluated pregnant women (96.9%).Only the study by Renz et al. 18 had all risk of bias criteria contemplated for avoidability, thus presenting the highest number of positive responses.Conversely, the study by Siqueira et al. 19 met none of the criteria, having the highest number of negative answers.

Figure 1
Flowchart of studies included in the systematic review and meta-analysis of gestational diabetes mellitus prevalence in Brazil between 2010 and 2021.

Table 1
Characteristics of studies included in the systematic review and meta-analysis of gestational diabetes mellitus prevalence in Brazil between 2010 and 2021.*** This study also used the WHO 1999 diagnostic criteria, whose prevalence was 27.48%;

Study (Year
# The study did not present the gestational diabetes mellitus prevalence in the scientific article.This indicator was calculated based on the number of women with gestational diabetes mellitus and the population sample; ## Descriptive prevalence study; ### This study also used the ADA 2010 diagnostic criteria, whose prevalence was 0.6%, performed at any time up to the 34th week of pregnancy. Cad. Saúde Pública 2024; 40(8):e00064919   Overall certainty of evidence rating was low.Quality assessment showed weaknesses in inconsistency and indirectness (Box 1).
The meta-analysis included all 32 articles to estimate the gestational diabetes mellitus pooled prevalence of 14% (95%CI: 11.0; 16.0) with a heterogeneity between studies (I 2 ) of 97.9% (p < 0.001) (Figure 2).Regarding publication bias, the Egger's test with a p-value of 0.003 and the funnel plot indicate its presence (Figure 3).To estimate the potential impact of publication bias on the gestational diabetes mellitus pooled prevalence, we performed a trim-and-fill test imputing two studies on the left side of the funnel plot, resulting in a pooled prevalence of 12.3% (95%CI: 8.8; 15.9).
As for diagnostic criteria, the gestational diabetes mellitus pooled prevalence was 15% (95%CI: 10.0; 20.0), 14% (95%CI: 11.0; 18.0), 15% (95%CI: 6.0; 24.0) and 10% (95%CI: 5.0; 15.0), respectively, for the IADPSG, IADPSG adapted, other criteria and unspecified criteria.Analysis by country region showed that most studies were conducted in the Southeast and South regions, with 14% (95%CI: 0.09; 0.18) and 13% (95%CI: 9.0; 16.0) gestational diabetes mellitus pooled prevalences, respectively.Northeast presented a pooled prevalence of 11% (95%CI: 5.0-18.0)and the Central-West, 9% (95%CI: 7.0; 11.0).* Although most studies were classified as high risk of bias according to Hoy et al. 14 , the sensitivity analysis revealed minimal disparity in the gestational diabetes mellitus prevalence between studies with low risk (0.12) and high risk (0.14) ratings.Thus, we deduced that the limitations of the weaker studies did not importantly bias the results.Consequently, we did not rate down the confidence rating; ** Considerable heterogeneity in results across studies was observed, ranging from 0.03 to 0.40.Consequently, we opted to downgrade the confidence level; *** Besides the high heterogeneity among studies, the inclusion of a large number of studies in this systematic review resulted in a narrow 95%CI range for prevalence (0.11; 0.16).We decided to not rate down the confidence rating; # Noticeable heterogeneity was observed in study characteristics, such as variations in diagnostic criteria, gestational age of the populations studied, and sample sizes.According to Hoy et al. 14 instrument, a large number of studies presented limitations in criteria related to external validity.We opted to downgrade the confidence level; ## Publication bias was verified using Egger's test (p = 0.003), as well as the funnel plot.However, the gestational diabetes mellitus pooled prevalence (14%) is included in the 95%CI of the trim-and-fill prevalence estimation (8.8; 15.9).Consequently, we decided to not rate down the confidence rating.
Finally, the results of the meta-regression analysis for random effects (Figure 4) showed that the variable "year of data collection" did not significantly contribute to heterogeneity, presenting a coefficient equal to -0.002 (95%CI: -0.009; 0.004) and a p-value of 0.439.

Discussion
This systematic review and meta-analysis estimated the gestational diabetes mellitus pooled prevalence in Brazil at 14% (95%CI: 11.0; 16.0) from analyzing 32 studies, totaling a sample of 21,942 pregnant women.Moreover, it assessed the pooled prevalence according to country region, the diagnostic criteria used and the risk of bias.
According to the Diabetes Atlas of the International Diabetes Federation (IDF) 7 , in 2021 the estimated gestational diabetes mellitus prevalence in South and Central America was 10.4% (95%CI: 10.1; 10.7), below the pooled prevalence found in this systematic review.A study conducted in Chile found an even lower prevalence, 7.6% (95%CI: 7.5; 7.8) 28 .Studies in countries like Argentina and Peru, in turn, observed a higher prevalence than those found in Brazil, 24.9% and 16%, respectively 29,30 .
A Brazilian study conducted with greater robustness (larger sample and low risk of bias) showed a prevalence of 20.8% 31 .Other studies with comparatively larger samples, but with a moderate risk of bias, presented greater variability, probably due to the sources of heterogeneity discussed later: 3.3% 32 , 10.8% 33 and 18,1% 34 .

Figure 2
Gestational diabetes mellitus prevalence forest plot of studies published in Brazil between 2010 and 2021.95%CI: 95% confidence interval; ES: effect size.
Importantly, this was the first systematic review and meta-analysis on gestational diabetes mellitus in the country.Previously, based on a cohort study 35 from 1991 to 1995, the 2006 Brazilian guidelines 36 cited a prevalence between only 2.4% (95%CI: 2.0; 2.9) and 7.2% (95%CI: 6.5; 7.9) according to 2000 ADA and 1999 WHO criteria, respectively.Conversely, the 2017 Brazilian consensus 1 points to a prevalence of around 18% (95%CI: 16.9; 19.0) based on a cohort study 8 using IADPSG criteria.Our study presents a considerably higher estimate than older investigations founded on previous diagnostic criteria and a similar, but lower, estimate to a newer research using the updated criteria.
Regarding pooled prevalences analyzed by region, the Northeast showed a pooled prevalence of 11%, due to the disparity between the studies with 20.8% 30 and 1.6% 37 values, and the Central-West of 9%, given the 28.2% 18 and 4.3% 38 values.A possible explanation for data variability is the asymmetry in socioeconomic conditions and access to health services between Brazilian regions, influencing the number of diagnoses.Screening is made difficult by factors such as housing condi-Cad.Saúde Pública 2024; 40(8):e00064919

Figure 3
Funnel plot with pseudo 95% confidence intervals on the ratio of pregnant women with gestational diabetes mellitus in Brazil between 2010-2021.ES: effect size; se(ES): standard error of the effect size.
tions, family income, schooling level, urbanization, water supply and sanitation thus increasing the chances of complications during pregnancy 37 .This hypotheses aligns with in a study conducted in India 39 , which pointed to a considerable variation in gestational diabetes mellitus prevalence by state, socioeconomic level and demographic factors, as well as the correlation of areas with few economic resources allocated to gestational diabetes mellitus screening with lower prevalence levels.Hence, socioeconomic and care factors may influence this decrease in regional prevalence.
As for the diagnostic criteria used, we observed a weakness in the studies homogeneity.A total of five different diagnostic criteria were identified in the analyzed articles, in addition to those lacking this information.IADPSG (five studies) and the adapted IADPSG (14 studies) were the most used, frequently performing the OGTT 75g in a period different from that established in the original instrument.The stratified meta-analysis found a higher pooled prevalence (15%; 95%CI: 10.0; 20.0) in articles that employed the original criterion and a lower pooled prevalence (14%; 95%CI: 11.0; 18.0), in those with some adaptation, showing a possible decrease in diagnostic sensitivity.Similarly, when comparing the IADPSG criterion with the 2010 ADA, other studies have found higher diagnostic rates with the former 40,41,42 , confirming its greater sensitivity.
Regarding risk of bias, although most of the articles (82.4%) analyzed presented moderate or high risk, proportional values were obtained among low, moderate and high risk.A gestational diabetes mellitus pooled prevalence of 12% was found among low-risk studies; of 14% among moderate-risk studies, and of 14% among high-risk studies.Representative sample (27 studies) and random or census selection (26 studies) were the most frequent risks of bias, whereas using different diagnostic methods for all participants occurred only once.Despite the importance of study quality for selecting the best evidence, the risk of bias was not a factor of great influence on distorting the results found.

Figure 4
Meta-regression analysis on the ratio of pregnant women with gestational diabetes mellitus and the year of data collection in the studies published in Brazil between 2010-2021.
Cad. Saúde Pública 2024; 40(8):e00064919 Study limitations include the disparity in the number of studies from different regions and the lack of detailed information about methodology and gestational diabetes mellitus measurement criteria in some articles.Thus, threshold value changes in identifying gestational diabetes mellitus would inevitably cause high heterogeneity in the results.Additionally, the meta-analysis included studies with small sample sizes, which may result in data with high analytical variability, and different designs (whether prospective or retrospective cohort, cross-sectional study, diagnostic or descriptive test).
Despite achieving the main study objective, we did not evaluate the factors that may influence gestational diabetes mellitus prevalence.Most studies have not evaluated the gestational diabetes mellitus effects on maternal and fetal outcomes and were conducted in Southeastern and Southern municipalities, causing a great risk of bias in data interpretation and generalization for other locations which were not included in the meta-analysis or had few articles analyzed in comparison.Similarly, none of the studies included in this systematic review used a national population base pointing to the need for new nationally representative research.
Despite these limitations, this is the first meta-analysis conducted in Brazil about gestational diabetes mellitus prevalence stratified by region and with analysis of risk of bias and methodological quality of the publications, helping with data interpretation.

Conclusion
This study provided evidence on estimated gestational diabetes mellitus occurrence in Brazil between 2010 and 2021.Data summarized in the meta-analysis showed a gestational diabetes mellitus pooled prevalence of 14%.Country region, the diagnostic criteria used and study quality influenced the resulting pooled prevalence indicator.However, the high heterogeneity between the studies hindered to summarize the findings.
To the best of our knowledge, this meta-analysis is the first to provide evidence on the national gestational diabetes mellitus pooled prevalence, a key factor in understanding and characterizing the epidemiology of the condition.Given the evidence generated, the issue may trigger greater interest in health managers to address the disease.The current national scenario requires planning to manage the condition.Screening and diagnosis, based on standardized criteria, as well as preventive actions for gestational diabetes mellitus control and adequate patient management could potentially reduce this disease's burden.

Table 1 (continued) Study (Year) State/Region Investigation period Study design Full sample Sample studied Prevalence (%) Diagnostic criteria Gestational age
ADA: American Diabetes Association; GTDG: Brazilian Diabetes and Pregnancy Task Force; IADPSG: International Association of Diabetes in Pregnancy Study Group; NI: not informed; WHO: World Health Organization.*This study also used the ADA 2010 diagnostic criteria, whose prevalence was 5.8%; ** Besides the IADPSG criteria, this study also used seven different adaptations from original IADPSG diagnostic criteria (prevalences of 2.7%; 12.7%;

Table 2
Risk of bias assessment of studies included in the systematic review and meta-analysis of gestational diabetes mellitus prevalence in Brazil between 2010 and 2021.

Table 3
Meta-analysis stratified by risk of bias, diagnostic criteria and country region with study data concerning gestational diabetes mellitus pooled prevalence in Brazil between 2010 and 2021.